Higher eukaryotes have many distinct esterases. Among the different types of esterases are those that act on carboxylic esters, also known as carboxylesterases. Carboxylesterases have been classified into three categories (A, B and C) on the basis of differential patters of inhibition by organophosphates (Myers et al. (1988) Mol. Biol. Evol. 5(2):113–119). Sequence analysis of a number of type-B carboxylesterase demonstrates their evolutionary interrelatedness. Members of the type B carboxylesterase family include acetylcholincarboxylesterases, mammalian cholincarboxylesterases, thyroglobulin, neuroligins, and mammalian bile salt activated lipases.
The type B family of carboxylesterase also includes vitamin K-dependent carboxylases. Vitamin K-dependent gamma-glutamyl carboxylases catalyze the posttranslational conversion of glutamic acid to gamma-carboxyglutamic acid, an amino acid critical to the function of the vitamin K-dependent blood coagulation proteins (Begley et al. (2000) J. Biol. Chem. 275:36245–36249). Incomplete gamma carboxylation of blood clotting factors is associated with poor coagulation.
For the gamma carboxylation event to occur, both vitamin K and the presence of a gamma carboxylation recognition site on the substrate are required. Gamma carboxyglutamic acid confers calcium binding ability upon the modified protein. For blood clotting factors, calcium binding results in a conformational change that exposes hydrophobic residues for interactions with membranes.
Although gamma carboxylation was a biochemical event first characterized in the mammalian blood clotting cascade, it has been found to have a more generalized applicability. For example, vitamin K-dependent gamma carboxylation of glutamate residues has also been detected for a variety of other proteins including bone proteins, PRGP1, PRGP2, and neuropeptides (Walker et al. (2000) J. Biol. Chem., December 7 epub ahead of print).